Role of Testosterone in Modulating Tau Pathogenesis in Females

睾酮在调节女性 Tau 发病机制中的作用

基本信息

批准号：
10685501
负责人：
Xu Chen
金额：
$ 56.64万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685501
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease risk Androgen Receptor Androgens Animals Anti-Inflammatory Agents Apolipoprotein E Apolipoproteins Astrocytes Biology Brain Cerebrospinal Fluid Clinical Clinical Data Cognitive deficits Collaborations Compensation Data Deposition Development Disease Disease Pathway Estrogens Female Functional disorder Gene Expression Genetic Goals Gonadal Steroid Hormones Hormones Human Impaired cognition Inflammation Intervention Knock-in Knock-in Mouse Knowledge Link Literature Mediating Metabolism Microglia Modeling Molecular Mus Neurodegenerative Disorders Neurons Neurosecretory Systems Operative Surgical Procedures Outcome Ovariectomy Pathogenesis Pathologic Pathology Pathway interactions Physiological Progesterone Publishing Receptor Signaling Regulation Reporting Reproductive Biology Research Research Personnel Risk Reduction Role Sex Differences Signal Transduction Stanolone Supplementation Synapses Tauopathies Testosterone Therapeutic Transgenic Mice Translational Research Woman Work brain cell capsule cell type clinical application cognitive function conditional knockout effective intervention effective therapy genetic manipulation high risk improved insight male men mouse model neuroimaging neuroinflammation neuronal survival neuroprotection novel pharmacologic precision medicine preclinical study programs protective effect receptor-mediated signaling reproductive senescence response sex single nucleus RNA-sequencing subcutaneous tau Proteins tau aggregation tau-1 therapeutic target transcriptome transcriptomics

项目摘要

PROJECT SUMMARY Alzheimer’s disease (AD) and other tau-mediated neurodegenerative diseases are characterized by aggregation and spread of pathological tau protein in the brain. Despite decades of research, effective interventions to these diseases are still lacking. It is well-evidenced that women typically show greater tau pathology than men on the AD trajectory; yet the reason for such sex differences is poorly understood. A better understanding of the mechanisms underlying the greater tau deposition in women can benefit all by informing causal pathways of disease and therapeutic targets and strategies that are optimal for each sex. Clinical evidence suggests that low testosterone levels correlate with poorer cognitive function and greater risk for AD. In particular, a recent study in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) revealed that women with lower testosterone tend to have higher levels of phosphorylated tau (p-tau) in cerebrospinal fluid (CSF), particularly among ApoE4 carriers. This suggest that lower testosterone levels that typically characterize women may predispose them to pathological tau, and contribute to sex differences observed in AD. To take these correlative findings to the necessary next step, our overall objectives are to establish the causal relationship between testosterone and tau in females, to explore the clinical applicability of testosterone therapy, and to elucidate the underlying molecular mechanisms. Given testosterone’s anti-inflammatory actions and neuroprotective effects on AD-related outcomes, we hypothesize that pharmacological induction of high testosterone protects against pathological tau accumulation and spread, diminishes neuroinflammation and ameliorates cognitive deficits associated with tau pathogenesis, particularly in ApoE4 females. Based on published preclinical studies on testosterone, we further hypothesize that the protective effects of testosterone are linked to androgen receptor signaling in astrocytes and neurons, leading to enhanced neuronal survival, synaptic integrity and reduces neuroinflammation. This project is a new direction in our research program: In collaboration with experts on reproductive biology and gene expression, we will combine our expertise in tau biology, sex hormones and transcriptomics to determine how testosterone modulates tau pathogenesis in a sex-specific manner. We will: 1) Determine how increase of testosterone levels affects tau pathogenesis in female tau transgenic mouse models with human ApoE4/E3 knock-in; 2) Elucidate the molecular mechanism underlying the protective effects of testosterone in ApoE4 females by single nucleus RNA sequencing, and determining the involvement of neuronal and astrocytic androgen receptor signaling. This project aims to close critical gaps in our understanding of mechanisms underlying sex differences in tau pathophysiology, and provide novel insights into the influence of androgen on molecular mechanisms central to AD pathogenesis. Results from the proposed research will address NIA strategic goals: understand the progression of Alzheimer’s (A), and identify potential therapeutic targets for the development of precision medicine treatments for men and women (D).

项目概要阿尔茨海默病 (AD) 和其他 tau 介导的神经退行性疾病的特点是聚集尽管经过数十年的研究，仍无法有效干预这些问题。有充分证据表明，女性通常比男性表现出更多的 tau 病理学特征。 AD 轨迹；但对这种性别差异的原因却知之甚少。女性体内 tau 沉积量增加的机制可以通过告知因果途径使所有人受益临床证据表明，对于每种性别来说，疾病和治疗目标以及策略的最佳水平较低。睾酮水平与较差的认知功能和较高的 AD 风险相关，特别是最近的一项研究。阿尔茨海默病神经影像倡议 (ADNI) 表明，睾酮水平较低的女性往往患有脑脊液 (CSF) 中磷酸化 tau (p-tau) 水平较高，尤其是 ApoE4 携带者。表明女性通常具有的较低睾酮水平可能会使她们容易患上病理性 tau 蛋白，并有助于在 AD 中观察到的性别差异。为了将这些相关发现带入下一步必要的步骤，我们的总体目标是建立女性睾酮和 tau 蛋白之间的因果关系，探索睾酮治疗的临床适用性，并阐明潜在的分子机制。睾酮的抗炎作用和对 AD 相关结果的神经保护作用，我们勇敢地说高睾酮的药理学诱导可防止病理性 tau 积累和扩散，减少神经炎症并改善与 tau 发病机制相关的认知缺陷，特别是根据已发表的关于睾酮的临床前研究，我们进一步指出睾酮的保护作用与星形胶质细胞和神经元中的雄激素受体信号传导有关，从而导致增强神经元存活、突触完整性并减少神经炎症。我们的研究计划：与生殖生物学和基因表达专家合作，我们将结合我们在 tau 生物学、性激素和转录组学方面的专业知识可确定睾酮如何调节 tau 我们将： 1) 确定睾酮水平的增加如何影响 tau 蛋白。人类 ApoE4/E3 敲入的雌性 tau 转基因小鼠模型的发病机制 2) 阐明分子机制；单核RNA对ApoE4女性睾酮保护作用的机制测序，并确定神经元和星形细胞雄激素受体信号传导的参与。该项目旨在弥合我们对 tau 性别差异背后机制的理解上的重大差距病理生理学，并提供关于雄激素对分子机制的影响的新见解 AD 发病机制。拟议研究的结果将解决 NIA 的战略目标：了解 AD 发病机制。阿尔茨海默病的进展 (A)，并确定潜在的治疗靶点以实现精准治疗男性和女性的药物治疗（D）。